Organ transplant patients who are immune-suppressed are at high risk to develop non-melanoma skin cancers (NMSC). Prevention of NMSC in this high risk population requires the development of effective drugs with minimal toxicity since these drugs are administered chronically. An FDA- approved drug has yet to be identified for use to prevent NMSC. We have developed a novel tissue-selective rexinoid, named UAB30, which acts as an agonist in epithelial tissues but not in liver. UAB30 is highly effective in multiple cancer prevention models while exhibiting minimal toxicity (especially lipid toxicity). UAB30 is currently evaluated in phase 1 human trials. Preliminary results (Core 3) show that UAB30 is highly effective in preventing the formation of papilloma, basal cell carcinoma, and squamous cell carcinoma in UVB-irradiated hairless mice. We have also shown that UAB30 up-regulates genes important for enhancing all-trans-retinoic acid biosynthesis in normal epithelium and in cancers. Thus, we hypothesize in this proposal that UAB30 (or other UAB30-like agonists) prevent NMSC by enhancing signaling through RXR-RAR heterodimers. In Aim 1, we propose studies to understand how rexinoids bind RXR and remodel the surface of the nuclear receptor to recruit coactivators. The importance of residues within the two putative molecular networks that bridge the rexinoid binding site to the coactivator binding site will be investigated using x-ray crystallography, Hydrogen-Deuterium Exchange Mass Spectrometry (HDX MS), and isothermal titration calorimetry (ITC). In Aim 2, we propose studies to understand if the molecular signatures of potency versus those of toxicity be revealed so that new 3rd -generation agonists are designed without toxicity. Structural studies on a series of methyl-derivatives of UAB30 have revealed a putative `hot-spot' in the ligand binding pocket that stimulates lipid biosynthesis and toxicity. We will examine the importance of this `hot-spot' by evaluating structures and dynamics of a series of potent rexinoids with known lipid profiles (potent rexinoids that induce lipid synthesis versus those that do not). A team of structural biologists with expertise in x-ray crystallography, mass spectrometry, thermodynamics, and biophysics has been assembled to address these aims. Project 2 provides information on the structure and dynamics of RXR, which we hypothesized, can be important for determining which rexinoids are potent and nontoxic. Project 2 will interact with Core 2 in designing new 3rd generation rexinoids, which will be evaluated in in vitro studies in Project 3 and in in vivo models in Core 3. The Program Integration section contains a complete developmental schema for 3rd generation rexinoids.